Melanoma is a serious form of skin cancer in humans. It arises from the pigment cells (melanocytes), usually in the skin. Melanoma is currently increasing at the fastest rate of all cancers in the United States. Without even including melanoma in-situ, it is the seventh most common serious cancer in the United States. There are projected to be 60,000 new cases of melanoma in the United States in 2006, with 7,600 deaths due to melanoma. This means, on average, about one person per hour will die in the U.S. due to this disease. It is the most common cancer in women aged 25-29 years old, it is second in malignancies of adulthood in terms of life-years lost and currently the prognosis for melanoma once it is disseminated is dismal.
The growth and metastasis of melanoma as well as its notorious resistance to therapy present major obstacles to its treatment. A growing number of genetic and epigenetic changes in melanomas impact genes associated with melanocyte development and maintenance, cell cycle control, resistance to apoptosis, angiogenic and metastatic capacity. Among the genetic changes commonly found in human melanomas are mutations in protein kinases of the MAPK family, indicating that signal transduction pathways have been largely modified in this tumor type. Specifically, the prevalence of activating mutations in B-RAF and N-Ras has been largely associated with the activation of downstream targets—MEK and in many cases ERK-MAPK. Constitutive activation of these kinases results in corresponding upregulation of their targets, including genes implicated in the development and maintenance of melanoma such as MITF, iNOS and cyclin D1.
In addition to changes in the MAPK signaling pathway, other pathways are deregulated in melanoma, for reasons as yet unknown. For example, a growing fraction of melanomas is recognized as carrying an inactive form of PTEN, a protein phosphatase implicated in the regulation of AKT signaling pathways and their downstream mTOR and p70S6 effectors. Upregulation of PKC and JNK has also been observed in melanoma. Other regulatory components that are modified in melanoma include cell cycle regulatory proteins, such as cyclin-dependent kinases (CDKN2A) CDK2, p16/CDK/pRb and cyclin D1.
Modifications were also recorded in MMP, proteases associated with tumor cells metastatic capacity and chaperones such as HSP90. The anti-apoptotic proteins such as Bcl2 and the transcription factors ATF1, AP1 and ATF2 also cooperate in conferring resistance to apoptosis and metastatic capacity on melanoma. The complexity of changes that take place in melanoma are further illustrated in the rewiring of key signal transduction pathways; for example, ERK causes upregulation of c-Jun and JNK activity. The transcription factor ATF2 has been suggested as a marker and possible target for this tumor type (Berger et al., Cancer Res 63:8103-7, 2003; and Bhoumik et al., PNAS 101:4222-7, 2004). Analysis of 544 human melanomas using tissue arrays revealed that nuclear localization of ATF2 is associated with poor prognosis, thereby pointing to the possibility that constitutively active ATF2 may contribute to the development and progression of human melanomas. Consistent with this possibility, inhibition of ATF2 function by means of a 50 amino acid peptide derived from ATF2 sensitized melanoma to apoptosis (Bhoumik et al., Clin Cancer Res 7:331-42, 2001) and inhibited growth and metastasis in mouse models (Bhoumik et al., Cancer Res 64:8222-30, 2004; and Bhoumik et al., J Clin Invest 110:643-50, 2002). ATF2 peptides elicit such effects by virtue of their ability to inhibit ATF2 concomitant with an increase in JNK and consequently c-Jun activities.